Skip to main content

Immunologische Aspekte bei depressiven Störungen

Immunological aspects of depressive disorders

Zusammenfassung

Neben dem Monoaminmangelkonzept als pathophysiologischem Korrelat der depressiven Störung wird zunehmend die Rolle der gesteigerten glutamatergen Neurotransmission diskutiert. Ursachen und Wechselwirkungen dieser Neurotransmitterveränderungen sind bisher allerdings nicht verstanden. In der vorliegenden Übersicht präsentieren wir ein Konzept, das aktuelle Befunde der Neurotransmitterfehlregulierung sowie immunologische und morphologische Befunde bei depressiven Störungen integriert. Mehrere ineinandergreifende Mechanismen scheinen von Bedeutung zu sein: Ursache des Serotoninmangels und gesteigerter glutamaterger Neurotransmission ist möglicherweise der Anstieg proinflammatorischer Zytokine. Eine Immunaktivierung mit gesteigerter Produktion proinflammatorischer Zytokine aktiviert das tryptophan- und serotoninabbauende Enzym Indolamin-2,3-Dioxygenase (IDO). Der gesteigerte Verbrauch von Serotonin und seinem Vorläufer Tryptophan aufgrund der IDO-Aktivierung kann die verringerte Verfügbarkeit von Serotonin bei Depression erklären. Auch bei entzündlichen somatischen Erkrankungen ist die depressive Stimmungslage mit einem Anstieg proinflammatorischer Zytokine und gesteigertem Verbrauch von Tryptophan assoziiert. Die Aktivierung von IDO durch proinflammatorische Zytokine führt darüber hinaus zur Produktion von glutamatergen Agonisten. Im zentralen Nervensystem (ZNS) wird IDO während entzündlicher Prozesse vor allem in Mikrogliazellen aktiviert. Deshalb ist das Astrozyten-Mikroglia-Gleichgewicht bei Depression von Bedeutung. Die beschriebene Verringerung von Astrozyten im ZNS depressiver Patienten kann sowohl die Gegenregulierung zur IDO-Aktivität in Mikrogliazellen hemmen, als auch eine Veränderung der glutamatergen Neurotransmission bewirken. Auf diesem Wege kann das Ungleichgewicht der Immunantwort, zusammen mit dem Astrozyten-Mikroglia-Ungleichgewicht zu einerseits Serotoninmangel und andererseits glutamaterger Überaktivität bei Depression führen. Die weitere Suche nach neuen antidepressiven Therapieverfahren sollte antientzündliche Substanzen berücksichtigen, zum Beispiel COX-2-Inhibitoren.

Summary

Beside the monoaminergic deficiency concept as a pathophysiological correlate of depressive disorder, the role of increased glutamatergic neurotransmission is increasingly being discussed. Causes and interactions of these neurotransmitter disturbances are not fully understood to date. This review presents a concept integrating actual findings of the neurotransmitter dysregulations with immunological and morphological findings in depressive disorder. Several intertwined mechanisms seem to be important: The common cause of serotonin deficiency and increased glutamatergic neurotransmission seems to be the increase of proinflammatory cytokines. Immune activation with increased production of proinflammatory cytokines activate the tryptophan- and serotonin-degradating enzyme indolamine-2,3-dioxygenase (IDO). The increased consumption of serotonin and its precursor tryptophan due to IDO activation may explain the reduced availability of serotonin in depression. In inflammatory somatic disorders, depressive mood is associated with an increase of proinflammatory cytokines and increased consumption of tryptophan. This activation of IDO by proinflammatory cytokines leads to the production of glutamatergic agonists. In the CNS, IDO is activated during inflammatory processes primarily in microglial cells. Therefore the astrocyte:microglial balance in depression is important. The observed decrease of astrocytes in the CNS of depressive patients may contribute to a regulatory fault in the activity of IDO in microglial cells but also can cause an alteration of the glutamatergic neurotransmission. By this mechanism, the dysbalance of the immune response and the astrocyte:microglia dysbalance may contribute to serotonergic deficiency and glutamatergic overproduction in depression. The further search for new antidepressant therapeutic mechanisms should take into regard anti-inflammatory substances, e.g. cyclo-oxygenase-2 (COX-2)-inhibitors.

This is a preview of subscription content, access via your institution.

Abb. 1
Abb. 2

Literatur

  1. Matussek N (1966) Neurobiologie und Depression. Med Monatsschr 3: 109–112

    Google Scholar 

  2. Coppen A, Swade C (1988) 5-HT and depression: the present position. In: Briley M, Fillion G (eds) New concepts in depression. MacMillan Press, London, pp 120–136

  3. Crane GE (1959) Cyloserine as an antidepressant agent. Am J Psychiatry 115: 1025–1026

    PubMed  CAS  Google Scholar 

  4. Maj J, Rogoz Z, Skuza G, Sowinska H (1992) Effects of MK-801 and antidepressant drugs in the forced swimming test in rats. Eur Neuropsychopharmacol 2: 37–41

    PubMed  CAS  Google Scholar 

  5. Trullas R, Skolnick P (1990) Functional antagonists at the NMDA receptor complex exhibit antidepressant actions. Eur J Pharmacol 185: 1–10

    PubMed  CAS  Google Scholar 

  6. Yilmaz A, Schulz D, Aksoy A, Canbeyli R (2002) Prolonged effect of an anesthetic dose of ketamine on behavioral despair. Pharmacol Biochem Behav 71: 341–344

    PubMed  CAS  Google Scholar 

  7. Ossowska G, Klenk-Majewska B, Szymczyk G (1997) The effect of NMDA antagonists on footshock-induced fighting behavior in chronically stressed rats. J Physiol Pharmacol 48: 127–135

    PubMed  CAS  Google Scholar 

  8. Kugaya A, Sanacora G (2005) Beyond monoamines: glutamatergic function in mood disorders. CNS Spectr 10: 808–819

    PubMed  Google Scholar 

  9. Zarate CA Jr, Singh JB, Quiroz JA et al. (2006) A double-blind, placebo-controlled study of memantine in the treatment of major depression. Am J Psychiatry 163: 153–155

    PubMed  Google Scholar 

  10. Huber TJ, Dietrich DE, Emrich HM (1999) Possible use of amantadine in depression. Pharmacopsychiatry 32: 47–55

    PubMed  CAS  Article  Google Scholar 

  11. Ostroff R, Gonzales M, Sanacora G (2005) Antidepressant effect of ketamine during ECT. Am J Psychiatry 162: 1385–1386

    PubMed  Google Scholar 

  12. Zarate CA Jr, Singh JB, Carlson PJ et al. (2006) A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 63: 856–864

    PubMed  CAS  Google Scholar 

  13. Frizzo ME, Dall’Onder LP, Dalcin KB, Souza DO (2004) Riluzole enhances glutamate uptake in rat astrocyte cultures. Cell Mol Neurobiol 24: 123–128

    PubMed  CAS  Google Scholar 

  14. Coric V, Milanovic S, Wasylink S et al. (2003) Beneficial effects of the antiglutamatergic agent riluzole in a patient diagnosed with obsessive-compulsive disorder and major depressive disorder. Psychopharmacology (Berl) 167: 219–220

    Google Scholar 

  15. Zarate CA Jr, Payne JL, Quiroz J et al. (2004) An open-label trial of riluzole in patients with treatment-resistant major depression. Am J Psychiatry 161: 171–174

    PubMed  Google Scholar 

  16. Yan QS, Reith ME, Jobe PC, Dailey JW (1997) Dizocilpine (MK-801) increases not only dopamine but also serotonin and norepinephrine transmissions in the nucleus accumbens as measured by microdialysis in freely moving rats. Brain Res 765: 149–158

    PubMed  CAS  Google Scholar 

  17. Martin P, Carlsson ML, Hjorth S (1998) Systemic PCP treatment elevates brain extracellular 5-HT: a microdialysis study in awake rats. Neuroreport 9: 2985–2988

    PubMed  CAS  Article  Google Scholar 

  18. Kim JS, Schmid-Burgk W, Claus D, Kornhuber HH (1982) Increased serum glutamate in depressed patients. Arch Psychiatr Nervenkr 232: 299–304

    PubMed  CAS  Google Scholar 

  19. Mauri MC, Ferrara A, Boscati L et al. (1998) Plasma and platelet amino acid concentrations in patients affected by major depression and under fluvoxamine treatment. Neuropsychobiology 37: 124–129

    PubMed  CAS  Google Scholar 

  20. Maes M, Song C, Lin A et al. (1998) The effects of psychological stress on humans: increased production of pro-inflammatory cytokines and a Th1-like response in stress-induced anxiety. Cytokine 10: 313–318

    PubMed  CAS  Google Scholar 

  21. Sanacora G, Gueorguieva R, Epperson CN et al. (2004) Subtype-specific alterations of gamma-aminobutyric acid and glutamate in patients with major depression. Arch Gen Psychiatry 61: 705–713

    PubMed  CAS  Google Scholar 

  22. Nowak G, Ordway GA, Paul IA (1995) Alterations in the N-methyl-D-aspartate (NMDA) receptor complex in the frontal cortex of suicide victims. Brain Res 675: 157–164

    PubMed  CAS  Google Scholar 

  23. Nudmamud-Thanoi S, Reynolds GP (2004) The NR1 subunit of the glutamate/NMDA receptor in the superior temporal cortex in schizophrenia and affective disorders. Neurosci Lett 372: 173–177

    PubMed  CAS  Google Scholar 

  24. Scarr E, Pavey G, Sundram S et al. (2003) Decreased hippocampal NMDA, but not kainate or AMPA receptors in bipolar disorder. Bipolar Disord 5: 257–264

    PubMed  CAS  Google Scholar 

  25. Martin A, Heyes MP, Salazar AM et al. (1992) Progressive slowing of reaction time and increasing cerebrospinal fluid concentrations of quinolinic acid in HIV-infected individuals. J Neuropsychiatry Clin Neurosci 4: 270–279

    PubMed  CAS  Google Scholar 

  26. Heyes MP, Brew BJ, Martin A et al. (1991) Quinolinic acid in cerebrospinal fluid and serum in HIV-1 infection: relationship to clinical and neurological status. Ann Neurol 29: 202–209

    PubMed  CAS  Google Scholar 

  27. Heyes MP, Saito K, Lackner A et al. (1998) Sources of the neurotoxin quinolinic acid in the brain of HIV-1-infected patients and retrovirus-infected macaques. FASEB J 12: 881–896

    PubMed  CAS  Google Scholar 

  28. Lapin IP (2003) Neurokynurenines (NEKY) as common neurochemical links of stress and anxiety. Adv Exp Med Biol 527: 121–125

    PubMed  CAS  Google Scholar 

  29. Wichers MC, Koek GH, Robaeys G et al. (2005) IDO and interferon-alpha-induced depressive symptoms: a shift in hypothesis from tryptophan depletion to neurotoxicity. Mol Psychiatry 10: 538–544

    PubMed  CAS  Google Scholar 

  30. Fedele E, Foster AC (1993) An evaluation of the role of extracellular amino acids in the delayed neurodegeneration induced by quinolinic acid in the rat striatum. Neuroscience 52: 911–917

    PubMed  CAS  Google Scholar 

  31. Chen Q, Surmeier DJ, Reiner A (1999) NMDA and non-NMDA receptor-mediated excitotoxicity are potentiated in cultured striatal neurons by prior chronic depolarization. Exp Neurol 159: 283–296

    PubMed  CAS  Google Scholar 

  32. Myint AM, Kim YK (2003) Cytokine-serotonin interaction through IDO: a neurodegeneration hypothesis of depression. Med Hypotheses 61: 519–525

    PubMed  CAS  Google Scholar 

  33. Aloisi F, Ria F, Adorini L (2000) Regulation of T-cell responses by CNS antigen-presenting cells: different roles for microglia and astrocytes. Immunol Today 21: 141–147

    PubMed  CAS  Google Scholar 

  34. Müller N, Hofschuster E, Ackenheil M et al. (1993) Investigations of the cellular immunity during depression and the free interval: evidence for an immune activation in affective psychosis. Prog Neuropsychopharmacol Biol Psychiatry 17: 713–730

    PubMed  Google Scholar 

  35. Maes M, Meltzer HY, Bosmans E et al. (1995) Increased plasma concentrations of interleukin-6, soluble interleukin-6, soluble interleukin-2 and transferrin receptor in major depression. J Affect Disord 34: 301–309

    PubMed  CAS  Google Scholar 

  36. Maes M, Meltzer HY, Buckley P, Bosmans E (1995) Plasma-soluble interleukin-2 and transferrin receptor in schizophrenia and major depression. Eur Arch Psychiatry Clin Neurosci 244: 325–329

    PubMed  CAS  Google Scholar 

  37. Müller N, Schwarz MJ (2002) Immunology in anxiety and depression. In: Kasper S, Boer JA den, Sitsen JMA (eds) Handbook of depression and anxiety. Marcel Dekker, New York, pp 267–288

  38. Mikova O, Yakimova R, Bosmans E et al. (2001) Increased serum tumor necrosis factor alpha concentrations in major depression and multiple sclerosis. Eur Neuropsychopharmacol 11: 203–208

    PubMed  CAS  Google Scholar 

  39. Herbert TB, Cohen S (1993) Depression and immunity: a meta-analytic review. Psychol Bull 113: 472–486

    PubMed  CAS  Google Scholar 

  40. Seidel A, Arolt V, Hunstiger M et al. (1996) Major depressive disorder is associated with elevated monocyte counts. Acta Psychiatr Scand 94: 198–204

    PubMed  CAS  Google Scholar 

  41. Rothermundt M, Arolt V, Fenker J et al. (2001) Different immune patterns in melancholic and non-melancholic major depression. Eur Arch Psychiatry Clin Neurosci 251: 90–97

    PubMed  CAS  Google Scholar 

  42. Maes M, Scharpe S, Meltzer HY et al. (1994) Increased neopterin and interferon-gamma secretion and lower availability of L-tryptophan in major depression: further evidence for an immune response. Psychiatry Res 54: 143–160

    PubMed  CAS  Google Scholar 

  43. Sluzewska A, Rybakowski J, Bosmans E et al. (1996) Indicators of immune activation in major depression. Psychiatry Res 64: 161–167

    PubMed  CAS  Google Scholar 

  44. Kim YK, Suh IB, Kim H et al. (2002) The plasma levels of interleukin-12 in schizophrenia, major depression, and bipolar mania: effects of psychotropic drugs. Mol Psychiatry 7: 1107–1114

    PubMed  CAS  Google Scholar 

  45. Maes M, Scharpe S, Meltzer HY et al. (1993) Relationships between interleukin-6 activity, acute phase proteins, and function of the hypothalamic-pituitary-adrenal axis in severe depression. Psychiatry Res 49: 11–27

    PubMed  CAS  Google Scholar 

  46. Berk M, Wadee AA, Kuschke RH, O’Neill-Kerr A (1997) Acute phase proteins in major depression. J Psychosom Res 43: 529–534

    PubMed  CAS  Google Scholar 

  47. Maes M, Bosmans E, De Jongh R et al. (1997) Increased serum IL-6 and IL-1 receptor antagonist concentrations in major depression and treatment resistant depression. Cytokine 9: 853–858

    PubMed  CAS  Google Scholar 

  48. Frommberger UH, Bauer J, Haselbauer P et al. (1997) Interleukin-6-(IL-6) plasma levels in depression and schizophrenia: comparison between the acute state and after remission. Eur Arch Psychiatry Clin Neurosci 247: 228–233

    PubMed  CAS  Google Scholar 

  49. Song C, Lin A, Bonaccorso S et al. (1998) The inflammatory response system and the availability of plasma tryptophan in patients with primary sleep disorders and major depression. J Affect Disord 49: 211–219

    PubMed  CAS  Google Scholar 

  50. Katila H, Appelberg B, Hurme M, Rimon R (1994) Plasma levels of interleukin-1 beta and interleukin-6 in schizophrenia, other psychoses, and affective disorders. Schizophr Res 12: 29–34

    PubMed  CAS  Google Scholar 

  51. Brambilla F, Maggioni M (1998) Blood levels of cytokines in elderly patients with major depressive disorder. Acta Psychiatr Scand 97: 309–313

    PubMed  CAS  Google Scholar 

  52. Ershler WB, Sun WH, Binkley N et al. (1993) Interleukin-6 and aging: blood levels and mononuclear cell production increase with advancing age and in vitro production is modifiable by dietary restriction. Lymphokine Cytokine Res 12: 225–230

    PubMed  CAS  Google Scholar 

  53. Haack M, Hinze-Selch D, Fenzel T et al. (1999) Plasma levels of cytokines and soluble cytokine receptors in psychiatric patients upon hospital admission: effects of confounding factors and diagnosis. J Psychiatr Res 33: 407–418

    PubMed  CAS  Google Scholar 

  54. Maes M (1995) Evidence for an immune response in major depression: a review and hypothesis. Prog Neuropsychopharmacol Biol Psychiatry 19: 11–38

    PubMed  CAS  Google Scholar 

  55. Schiepers OJ, Wichers MC, Maes M (2005) Cytokines and major depression. Prog Neuropsychopharmacol Biol Psychiatry 29: 201–217

    PubMed  CAS  Google Scholar 

  56. Duch DS, Woolf JH, Nichol CA et al. (1984) Urinary excretion of biopterin and neopterin in psychiatric disorders. Psychiatry Res 11: 83–89

    PubMed  CAS  Google Scholar 

  57. Dunbar PR, Hill J, Neale TJ, Mellsop GW (1992) Neopterin measurement provides evidence of altered cell-mediated immunity in patients with depression, but not with schizophrenia. Psychol Med 22: 1051–1057

    PubMed  CAS  Article  Google Scholar 

  58. Bonaccorso S, Lin AH, Verkerk R et al. (1998) Immune markers in fibromyalgia: comparison with major depressed patients and normal volunteers. J Affect Disord 48: 75–82

    PubMed  CAS  Google Scholar 

  59. Müller N, Riedel M, Schwarz MJ, Engel RR (2005) Clinical effects of COX-2 inhibitors on cognition in schizophrenia. Eur Arch Psychiatry Clin Neurosci 255: 149–151

    PubMed  Google Scholar 

  60. Weiss G, Murr C, Zoller H et al. (1999) Modulation of neopterin formation and tryptophan degradation by Th1- and Th2-derived cytokines in human monocytic cells. Clin Exp Immunol 116: 435–440

    PubMed  CAS  Google Scholar 

  61. Braun D, Longman RS, Albert ML (2005) A two-step induction of indoleamine 2,3 dioxygenase (IDO) activity during dendritic-cell maturation. Blood 106: 2375–2381

    PubMed  CAS  Google Scholar 

  62. Robinson CM, Hale PT, Carlin JM (2005) The role of IFN-gamma and TNF-alpha-responsive regulatory elements in the synergistic induction of indoleamine dioxygenase. J Interferon Cytokine Res 25: 20–30

    PubMed  CAS  Google Scholar 

  63. Carlin JM, Ozaki Y, Byrne GI et al. (1989) Interferons and indoleamine 2,3-dioxygenase: role in antimicrobial and antitumor effects. Experientia 45: 535–541

    PubMed  CAS  Google Scholar 

  64. Taylor MW, Feng GS (1991) Relationship between interferon-gamma, indoleamine 2,3-dioxygenase, and tryptophan catabolism. FASEB J 5: 2516–2522

    PubMed  CAS  Google Scholar 

  65. Grohmann U, Fallarino F, Puccetti P (2003) Tolerance, DCs and tryptophan: much ado about IDO. Trends Immunol 24: 242–248

    PubMed  CAS  Google Scholar 

  66. Mellor AL, Munn DH (1999) Tryptophan catabolism and T-cell tolerance: immunosuppression by starvation? Immunol Today 20: 469–473

    PubMed  CAS  Google Scholar 

  67. Munn DH, Shafizadeh E, Attwood JT et al. (1999) Inhibition of T cell proliferation by macrophage tryptophan catabolism. J Exp Med 189: 1363–1372

    PubMed  CAS  Google Scholar 

  68. Saito K, Crowley JS, Markey SP, Heyes MP (1993) A mechanism for increased quinolinic acid formation following acute systemic immune stimulation. J Biol Chem 268: 15496–15503

    PubMed  CAS  Google Scholar 

  69. Alberati GD, Ricciardi CP, Kohler C, Cesura AM (1996) Regulation of the kynurenine metabolic pathway by interferon-gamma in murine cloned macrophages and microglial cells. J Neurochem 66: 996–1004

    Article  Google Scholar 

  70. Rosa-Neto P, Diksic M, Okazawa H et al. (2004) Measurement of brain regional alpha-[11C]methyl-L-tryptophan trapping as a measure of serotonin synthesis in medication-free patients with major depression. Arch Gen Psychiatry 61: 556–563

    PubMed  CAS  Google Scholar 

  71. Leyton M, Paquette V, Gravel P et al. (2006) alpha-[(11)C]Methyl-l-tryptophan trapping in the orbital and ventral medial prefrontal cortex of suicide attempters. Eur Neuropsychopharmacol 16: 220–223

    PubMed  CAS  Google Scholar 

  72. Dantzer R (2001) Cytokine-induced sickness behavior: where do we stand? Brain Behav Immun 15: 7–24

    PubMed  CAS  Google Scholar 

  73. Reichenberg A, Yirmiya R, Schuld A et al. (2001) Cytokine-associated emotional and cognitive disturbances in humans. Arch Gen Psychiatry 58: 445–452

    PubMed  CAS  Google Scholar 

  74. Reichenberg A, Kraus T, Haack M et al. (2002) Endotoxin-induced changes in food consumption in healthy volunteers are associated with TNF-alpha and IL-6 secretion. Psychoneuroendocrinology 27: 945–956

    PubMed  CAS  Google Scholar 

  75. Raison CL, Capuron L, Miller AH (2006) Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol 27: 24–31

    PubMed  CAS  Google Scholar 

  76. Bonaccorso S, Meltzer HY, Maes M (2000) Psychological and behavioral effects of interferons. Curr Opin Psychiatrie 13: 673–677

    Google Scholar 

  77. Schäfer M, Horn M, Schmidt F et al. (2004) Correlation between sICAM-1 and depressive symptoms during adjuvant treatment of melanoma with interferon-alpha. Brain Behav Immun 18: 555–562

    Google Scholar 

  78. Hauser P, Khosla J, Aurora H et al. (2002) A prospective study of the incidence and open-label treatment of interferon-induced major depressive disorder in patients with hepatitis C. Mol Psychiatry 7: 942–947

    PubMed  CAS  Google Scholar 

  79. Bonaccorso S, Marino V, Puzella A et al. (2002) Increased depressive ratings in patients with hepatitis C receiving interferon-alpha-based immunotherapy are related to interferon-alpha-induced changes in the serotonergic system. J Clin Psychopharmacol 22: 86–90

    PubMed  CAS  Google Scholar 

  80. Capuron L, Ravaud A, Neveu PJ et al. (2002) Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy. Mol Psychiatry 7: 468–473

    PubMed  CAS  Google Scholar 

  81. Capuron L, Neurauter G, Musselman DL et al. (2003) Interferon-alpha-induced changes in tryptophan metabolism. relationship to depression and paroxetine treatment. Biol Psychiatry 54: 906–914

    PubMed  CAS  Google Scholar 

  82. Amirkhani A, Rajda C, Arvidsson B et al. (2005) Interferon-beta affects the tryptophan metabolism in multiple sclerosis patients. Eur J Neurol 12: 625–631

    PubMed  CAS  Google Scholar 

  83. Patten SB, Francis G, Metz LM et al. (2005) The relationship between depression and interferon beta-1a therapy in patients with multiple sclerosis. Mult Scler 11: 175–181

    PubMed  CAS  Google Scholar 

  84. Marzi M, Vigano A, Trabattoni D et al. (1996) Characterization of type 1 and type 2 cytokine production profile in physiologic and pathologic human pregnancy. Clin Exp Immunol 106: 127–133

    PubMed  CAS  Google Scholar 

  85. Maes M, Verkerk R, Bonaccorso S et al. (2002) Depressive and anxiety symptoms in the early puerperium are related to increased degradation of tryptophan into kynurenine, a phenomenon which is related to immune activation. Life Sci 71: 1837–1848

    PubMed  CAS  Google Scholar 

  86. Josefsson A, Berg G, Nordin C, Sydsjo G (2001) Prevalence of depressive symptoms in late pregnancy and postpartum. Acta Obstet Gynecol Scand 80: 251–255

    PubMed  CAS  Google Scholar 

  87. O’Hara MW, Swain AM (1996) Rates and risk of post-partum depression – a meta-analysis. In Rev Psychiatry 8: 37–54

    Google Scholar 

  88. Kohl C, Walch T, Huber R et al. (2005) Measurement of tryptophan, kynurenine and neopterin in women with and without postpartum blues. J Affect Disord 86: 135–142

    PubMed  CAS  Google Scholar 

  89. Gard PR, Handley SL, Parsons AD, Waldron G (1986) A multivariate investigation of postpartum mood disturbance. Br J Psychiatry 148: 567–575

    PubMed  CAS  Google Scholar 

  90. Abou-Saleh MT, Ghubash R, Karim L et al. (1999) The role of pterins and related factors in the biology of early postpartum depression. Eur Neuropsychopharmacol 9: 295–300

    PubMed  CAS  Google Scholar 

  91. Linnoila M, Whorton AR, Rubinow DR et al. (1983) CSF prostaglandin levels in depressed and schizophrenic patients. Arch Gen Psychiatry 40: 405–406

    PubMed  CAS  Google Scholar 

  92. Calabrese JR, Skwerer RG, Barna B et al. (1986) Depression, immunocompetence, and prostaglandins of the E series. Psychiatry Res 17: 41–47

    PubMed  CAS  Google Scholar 

  93. Ohishi K, Ueno R, Nishino S et al. (1988) Increased level of salivary prostaglandins in patients with major depression. Biol Psychiatry 23: 326–334

    PubMed  CAS  Google Scholar 

  94. Mtabaji JP, Manku MS, Horrobin DF (1977) Actions of the tricyclic antidepressant clomipramine on responses to pressor agents. Interactions with prostaglandin E2. Prostaglandins 14: 125–132

    PubMed  CAS  Google Scholar 

  95. Yaron I, Shirazi I, Judovich R et al. (1999) Fluoxetine and amitriptyline inhibit nitric oxide, prostaglandin E2, and hyaluronic acid production in human synovial cells and synovial tissue cultures. Arthritis Rheum 42: 2561–2568

    PubMed  CAS  Google Scholar 

  96. Paykel ES, Myers JK, Dienelt MN et al. (1969) Life events and depression. A controlled study. Arch Gen Psychiatry 21: 753–760

    PubMed  CAS  Google Scholar 

  97. Hasler G, Drevets WC, Manji HK, Charney DS (2004) Discovering endophenotypes for major depression. Neuropsychopharmacology 29: 1765–1781

    PubMed  CAS  Google Scholar 

  98. Roy A, Pickar D, Paul S et al. (1987) CSF corticotropin-releasing hormone in depressed patients and normal control subjects. Am J Psychiatry 144: 641–645

    PubMed  CAS  Google Scholar 

  99. Burke HM, Davis MC, Otte C, Mohr DC (2005) Depression and cortisol responses to psychological stress: a meta-analysis. Psychoneuroendocrinology 30: 846–856

    PubMed  CAS  Google Scholar 

  100. Salas MA, Evans SW, Levell MJ, Whicher JT (1990) Interleukin-6 and ACTH act synergistically to stimulate the release of corticosterone from adrenal gland cells. Clin Exp Immunol 79: 470–473

    PubMed  CAS  Article  Google Scholar 

  101. Zhou D, Kusnecov AW, Shurin MR et al. (1993) Exposure to physical and psychological stressors elevates plasma interleukin 6: relationship to the activation of hypothalamic-pituitary-adrenal axis. Endocrinology 133: 2523–2530

    PubMed  CAS  Google Scholar 

  102. Miyahara S, Komori T, Fujiwara R et al. (2000) Effects of repeated stress on expression of interleukin-6 (IL-6) and IL-6 receptor mRNAs in rat hypothalamus and midbrain. Life Sci 66: L93–L98

    Google Scholar 

  103. Besedovsky H, Rey A del, Sorkin E, Dinarello CA (1986) Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones. Science 233: 652–654

    PubMed  CAS  Google Scholar 

  104. Berkenbosch F, Oers J van, Rey A del et al. (1987) Corticotropin-releasing factor-producing neurons in the rat activated by interleukin-1. Science 238: 524–526

    PubMed  CAS  Google Scholar 

  105. Sundar SK, Cierpial MA, Kilts C et al. (1990) Brain IL-1-induced immunosuppression occurs through activation of both pituitary-adrenal axis and sympathetic nervous system by corticotropin-releasing factor. J Neurosci 10: 3701–3706

    PubMed  CAS  Google Scholar 

  106. Weiss JM, Quan N, Sundar SK (1994) Immunological consequences of Interleukin-1 in the brain. Neuropsychopharmacol 10: 833

    Google Scholar 

  107. Plata-Salaman CR (1991) Immunoregulators in the nervous system. Neurosci Biobehav Rev 15: 185–215

    PubMed  CAS  Google Scholar 

  108. O’brien SM, Scott LV, Dinan TG (2004) Cytokines: abnormalities in major depression and implications for pharmacological treatment. Hum Psychopharmacol 19: 397–403

    Google Scholar 

  109. Pugh CR, Nguyen KT, Gonyea JL et al. (1999) Role of interleukin-1 beta in impairment of contextual fear conditioning caused by social isolation. Behav Brain Res 106: 109–118

    PubMed  CAS  Google Scholar 

  110. Nguyen KT, Deak T, Owens SM et al. (1998) Exposure to acute stress induces brain interleukin-1beta protein in the rat. J Neurosci 18: 2239–2246

    PubMed  CAS  Google Scholar 

  111. Madrigal JL, Garcia-Bueno B, Moro MA et al. (2003) Relationship between cyclooxygenase-2 and nitric oxide synthase-2 in rat cortex after stress. Eur J Neurosci 18: 1701–1705

    PubMed  Google Scholar 

  112. Sapolsky RM (1985) A mechanism for glucocorticoid toxicity in the hippocampus: increased neuronal vulnerability to metabolic insults. J Neurosci 5: 1228–1232

    PubMed  CAS  Google Scholar 

  113. Woolley CS, Gould E, McEwen BS (1990) Exposure to excess glucocorticoids alters dendritic morphology of adult hippocampal pyramidal neurons. Brain Res 531: 225–231

    PubMed  CAS  Google Scholar 

  114. Moghaddam B, Bolinao ML, Stein-Behrens B, Sapolsky R (1994) Glucocorticoids mediate the stress-induced extracellular accumulation of glutamate. Brain Res 655: 251–254

    PubMed  CAS  Google Scholar 

  115. Stein-Behrens BA, Lin WJ, Sapolsky RM (1994) Physiological elevations of glucocorticoids potentiate glutamate accumulation in the hippocampus. J Neurochem 63: 596–602

    PubMed  CAS  Article  Google Scholar 

  116. Takahashi T, Kimoto T, Tanabe N et al. (2002) Corticosterone acutely prolonged N-methyl-d-aspartate receptor-mediated Ca2+ elevation in cultured rat hippocampal neurons. J Neurochem 83: 1441–1451

    PubMed  CAS  Google Scholar 

  117. Nair A, Bonneau RH (2006) Stress-induced elevation of glucocorticoids increases microglia proliferation through NMDA receptor activation. J Neuroimmunol 171: 72–85

    PubMed  CAS  Google Scholar 

  118. Müller N, Schwarz MJ (2003) Role of the cytokine network in major psychoses. In: Hertz L (ed) Non-neuronal cells of the nervous system: function and dysfunction. Elsevier, Amsterdam, pp 999–1031

  119. Xiao BG, Link H (1999) Is there a balance between microglia and astrocytes in regulating Th1/Th2-cell responses and neuropathologies? Immunol Today 20: 477–479

    PubMed  CAS  Google Scholar 

  120. Cotter D, Pariante C, Rajkowska G (2002) Glial pathology in major psychiatric disorders. In: Agam G, Belmaker RH, Everall I (eds) The post-mortem brain in psychiatric research. Kluwer Acad Pub, Boston, pp 291–324

  121. Ongur D, Drevets WC, Price JL (1998) Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc Natl Acad Sci U S A 95: 13290–13295

    PubMed  CAS  Google Scholar 

  122. Rajkowska G, Miguel-Hidalgo JJ, Wei J et al. (1999) Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol Psychiatry 45: 1085–1098

    PubMed  CAS  Google Scholar 

  123. Rajkowska G, Halaris A, Selemon LD (2001) Reductions in neuronal and glial density characterize the dorsolateral prefrontal cortex in bipolar disorder. Biol Psychiatry 49: 741–752

    PubMed  CAS  Google Scholar 

  124. Rajkowska G (2003) Depression: what we can learn from postmortem studies. Neuroscientist 9: 273–284

    PubMed  Google Scholar 

  125. Johnston-Wilson NL, Sims CD, Hofmann J-P et al. (2000) Disease-specific alterations in frontal cortex brain proteins in schizophrenia, bipolar disorder, and major depressive disorder. Mol Psychiatry 5: 142–149

    PubMed  CAS  Google Scholar 

  126. Miguel-Hidalgo JJ, Baucom C, Dilley G et al. (2000) Glial fibrillary acidic protein immunoreactivity in the prefrontal cortex distinguishes younger from older adults in major depressive disorder. Biol Psychiatry 48: 861–873

    PubMed  CAS  Google Scholar 

  127. Si X, Miguel-Hidalgo JJ, O’Dwyer G et al. (2004) Age-dependent reductions in the level of glial fibrillary acidic protein in the prefrontal cortex in major depression. Neuropsychopharmacology 29: 2088–2096

    PubMed  CAS  Google Scholar 

  128. Davis S, Thomas A, Perry R et al. (2002) Glial fibrillary acidic protein in late life major depressive disorder: an immunocytochemical study. J Neurol Neurosurg Psychiatry 73: 556–560

    PubMed  CAS  Google Scholar 

  129. Fatemi SH, Laurence JA, Raghi-Niknam M et al. (2004) Glial fibrillary acidic protein is reduced in cerebellum of subjects with major depression, but not schizophrenia. Schizophr Res 69: 317–323

    PubMed  Google Scholar 

  130. Rajkowska G (2005) Astroglia in the cortex of schizophrenics: Histopathology finding. World J Biol Psychiatry 6: 74

    Google Scholar 

  131. Choudary PV, Molnar M, Evans SJ et al. (2005) Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression. Proc Natl Acad Sci U S A 102: 15653–15658

    PubMed  CAS  Google Scholar 

  132. Gegelashvili G, Robinson MB, Trotti D, Rauen T (2001) Regulation of glutamate transporters in health and disease. Prog Brain Res 132: 267–286

    PubMed  CAS  Article  Google Scholar 

  133. Auger C, Attwell D (2000) Fast removal of synaptic glutamate by postsynaptic transporters. Neuron 28: 547–558

    PubMed  CAS  Google Scholar 

  134. Danbolt NC (2001) Glutamate uptake. Prog Neurobiol 65: 1–105

    PubMed  CAS  Google Scholar 

  135. Maes M, Song C, Lin AH et al. (1999) Negative immunoregulatory effects of antidepressants: inhibition of interferon-gamma and stimulation of interleukin-10 secretion. Neuropsychopharmacology 20: 370–379

    PubMed  CAS  Google Scholar 

  136. Seidel A, Arolt V, Hunstiger M et al. (1995) Cytokine production and serum proteins in depression. Scand J Immunol 41: 534–538

    PubMed  CAS  Google Scholar 

  137. Bengtsson BO, Zhu J, Thorell LH et al. (1992) Effects of zimeldine and its metabolites, clomipramine, imipramine and maprotiline in experimental allergic neuritis in Lewis rats. J Neuroimmunol 39: 109–122

    PubMed  CAS  Google Scholar 

  138. Song C, Leonard BE (1994) An acute phase protein response in the olfactory bulbectomised rat: effect of sertraline treatment. Med Sci Res 22: 313–314

    CAS  Google Scholar 

  139. Zhu J, Bengtsson BO, Mix E et al. (1994) Effect of monoamine reuptake inhibiting antidepressants on major histocompatibility complex expression on macrophages in normal rats and rats with experimental allergic neuritis (EAN). Immunopharmacology 27: 225–244

    PubMed  CAS  Google Scholar 

  140. Lanquillon S, Krieg JC, Bening-Abu-Shach U, Vedder H (2000) Cytokine production and treatment response in major depressive disorder. Neuropsychopharmacology 22: 370–379

    PubMed  CAS  Google Scholar 

  141. Kenis G, Maes M (2002) Effects of antidepressants on the production of cytokines. Int J Neuropsychopharmacol 5: 401–412

    PubMed  CAS  Google Scholar 

  142. Sluzewska A, Rybakowski JK, Laciak M et al. (1995) Interleukin-6 serum levels in depressed patients before and after treatment with fluoxetine. Ann N Y Acad Sci 762: 474–476

    PubMed  CAS  Article  Google Scholar 

  143. Pollak Y, Yirmiya R (2002) Cytokine-induced changes in mood and behaviour: implications for ‚depression due to a general medical condition’, immunotherapy and antidepressive treatment. Int J Neuropsychopharmacol 5: 389–399

    PubMed  CAS  Google Scholar 

  144. Hestad KA, Tonseth S, Stoen CD et al. (2003) Raised plasma levels of tumor necrosis factor alpha in patients with depression: normalization during electroconvulsive therapy. J ECT 19: 183–188

    PubMed  Google Scholar 

  145. Dimitrov S, Lange T, Tieken S et al. (2004) Sleep associated regulation of T helper 1/T helper 2 cytokine balance in humans. Brain Behav Immun 18: 341–348

    PubMed  CAS  Google Scholar 

  146. Casolini P, Catalani A, Zuena AR, Angelucci L (2002) Inhibition of COX-2 reduces the age-dependent increase of hippocampal inflammatory markers, corticosterone secretion, and behavioral impairments in the rat. J Neurosci Res 68: 337–343

    PubMed  CAS  Google Scholar 

  147. Hu F, Wang X, Pace TW et al. (2005) Inhibition of COX-2 by celecoxib enhances glucocorticoid receptor function. Mol Psychiatry 10: 426–428

    PubMed  CAS  Google Scholar 

  148. Song C, Leonard BE (eds) (2000) Fundamentals of psychoneuroimmunology. J Wiley and Sons, Chichester, New York

  149. Cao C, Matsumura K, Ozaki M, Watanabe Y (1999) Lipopolysaccharide injected into the cerebral ventricle evokes fever through induction of cyclooxygenase-2 in brain endothelial cells. J Neurosci 19: 716–725

    PubMed  CAS  Google Scholar 

  150. Sandrini M, Vitale G, Pini LA (2002) Effect of rofecoxib on nociception and the serotonin system in the rat brain. Inflamm Res 51: 154–159

    PubMed  CAS  Google Scholar 

  151. Salzberg-Brenhouse HC, Chen EY, Emerich DF et al. (2003) Inhibitors of cyclooxygenase-2, but not cyclooxygenase-1 provide structural and functional protection against quinolinic acid-induced neurodegeneration. J Pharmacol Exp Ther 306: 218–228

    PubMed  CAS  Google Scholar 

  152. Collantes-Esteves E, Fernandez-Perrez Ch (2003) Improved self-control of ostheoarthritis pain and self-reported health status in non-responders to celecoxib switched to rofecoxib: results of PAVIA, an open-label post-marketing survey in spain. Curr Med Res Opin 19: 402–410

    Google Scholar 

  153. Müller N, Schwarz MJ, Dehning S et al. (2006) The Cyclo-oxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: Results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Mol Psychiatry 11: 680–684

    PubMed  Google Scholar 

Download references

Interessenkonflikt

Der korrespondierende Autor weist auf folgende Beziehung hin: Die Autoren haben die therapeutische Anwendung der COX-2-Inhibition bei psychiatrischen Indikationen zum Patentschutz eingereicht.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to N. Müller.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Müller, N., Schwarz, M. Immunologische Aspekte bei depressiven Störungen. Nervenarzt 78, 1261–1273 (2007). https://doi.org/10.1007/s00115-007-2311-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00115-007-2311-3

Schlüsselwörter

  • Depression
  • Glutamat
  • Indolamin-2,3-Dioxygenase
  • Mikroglia
  • Psychoneuroimmunologie
  • Serotonin

Keywords

  • Depression
  • Glutamate
  • Indolamine-2,3-dioxygenase
  • Microglia
  • Psychoneuroimmunology
  • Serotonin